An observational study has found that patients with chronic liver disease (CLD) who used aspirin or a non-aspirin nonsteroidal anti-inflammatory drug (NSAID) had a reduced risk of developing hepatocellular carcinoma (HCC) and a reduced risk of dying from CLD compared to those who did not use either aspirin or an NSAID. Risk factors for both HCC and CLD included being obese, smoking, and diabetes. The study was published yesterday in the Journal of the National Cancer Institute.

Participants in the study who reported using both aspirin and non-aspirin NSAIDs over the course of 1 year reduced their risk of developing HCC by 36% and had a 57% reduced risk of death from CLD compared to those who used neither NSAIDs nor aspirin. The reduced risk of HCC was seen regardless of whether participants took the drugs daily, weekly, or monthly.

Those who took aspirin regularly, regardless of additional NSAID use, had a 41% reduced risk of developing hepatocellular carcinoma (HCC) compared to those who did not use aspirin. Those who took aspirin also had a 45% reduction in risk of death from their CLD. The participants who took only aspirin, without additional reported NSAID use had an even greater reduction in risk of HCC—49% compared to those who did not take aspirin, and a 50% reduction in CLD mortality.

Regular use of other NSAIDS did not reduce HCC development. A 26% reduction in the risk of dying from CLD was seen among those who took NSAIDS, regardless of concurrent aspirin use, but this result was only statistically significant when the NSAID was taken monthly, not weekly or daily.

While HCC is relatively rare, occurring in fewer than 10 per 100,000 people per year, CLD is more frequent and is among the top 10 causes of death in adults between the ages of 45 to 75, according to the National Institutes of Health (NIH).

Vikrant V. Sahasrabuddhe, MD, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute, and colleagues compiled a cohort of 300,504 men and women 50 to 71 years of age who were part of the NIH-AARP Diet and Health Study and analyzed their aspirin and other NSAID use along with their cancer status. Almost three-fourths of the cohort reported aspirin use and approximately one-half reported using non-aspirin NSAIDs. There were 250 cases of HCC among the subjects and 428 deaths due to CLD. The follow-up period was 10 to 12 years.

This is the first link between aspirin and NSAID use and HCC development. Previous studies have demonstrated that regular aspirin use decreases the risk of colon cancer and may reduce the risk of death from cancer overall. Both aspirin and other NSAIDs may work by tempering inflammation which may have an antitumor effect. The limitation of the current study is a lack of information on the risk factors for CLD and HCC among the participants. The database used had no information on the hepatitis B and C status of the participants, which is directly linked to CLD. The study also did not have information on the dosage of the aspirin and NSAIDs use nor information on gastrointestinal bleeding, a major risk of long-term use of these medications.

Aspirin is prescribed to many men and women age 50 and over as a preventive measure against cardiovascular and cerebrovascular diseases, said Sahasrabuddhe. Aspirin and NSAIDs are also routinely used for arthritis musculoskeletal disorders and general pain relief. “Many of these patients may have or may be at risk of chronic liver disease, and our results suggest that users of NSAIDs may be at lower risk of HCC or death due to CLD,” said Sahasrabuddhe.

However, most CLD patients are advised to avoid any NSAIDs because of the risk of bleeding, said Isra G. Levy, MB, BCh, MSc, who co-authored the accompanying editorial on this study with Carolyn P. Pim, MD, both of whom are from of the department of epidemiology and community medicine at the University of Ottawa in Canada.

The editorial emphasizes that the major causes of CLD and HCC are hepatitis B and C viral infections as well as alcohol, for which there are many preventive measures such as hepatitis B and C immunization. In higher-income countries, alcohol abuse and risk factors such as obesity and diabetes are contributors to HCC numbers rather than hepatitis rates.

In order for aspirin to be practically useful, said Levy, “patients and their physicians would need to weigh potential benefits of chemoprevention against potential risks. The study provides information relating to potential benefits, but none regarding potential risks.”

Levy and Pim conclude that although novel ways to prevent HCC should be studied, focusing on improving immunization and other types of interventions known to prevent CLD and HCC should be a priority. “There is much we already know about how to prevent liver disease and cancer. While we study new possibilities, let’s also keep focused on what we already know,” state Levy and Pim. Levy cites four ways to prevent CLD, as previously suggested in a review by Thomas Riley, MD, of Penn State University: abstain from or only moderately consume alcohol, get vaccinated against hepatitis A and B, avoid hepatotoxins including NSAIDs and herbal products, and be physically active and maintain a healthy weight.

But Sahasrabuddhe emphasized that because a hepatitis B vaccine will not benefit those already chronically infected with the hepatitis B virus and because there is no vaccine for hepatitis C, “it is important to examine other means of trying to decrease risk of liver cancer,” adding that “this underscores the importance of conducting research on chemoprevention by commonly used drugs such as NSAIDs.”

While hard to estimate, hepatitis B virus confers an approximate 10% risk of HCC over 5 years in western countries. Those with alcohol-related cirrhosis have approximately an 8% chance of developing HCC.

Sahasrabuddhe and colleagues are currently assessing the risk of both HCC and CLD associated with NSAID intake in other large-scale cohort studies to confirm the current findings.

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